JULY 2011 • WWW.ECARDIOLOGYNEWS.COM HYPERTENSION 17

eraged 30 years, while the controls’ aver- and 17% in the controls. Women in both fined as a spot urine protein level of creased risk for hypertension at their fol- age age was 29 years. The index pregnan- groups had a similar average BMI, 29.9 more than 0.15 g/L, was 11% in the low-up screening examination, compared cy was the first pregnancy for 80% of the and 26.2 kg/m2, re- women with a his- with the control women, Dr. Drost re- women with preeclampsia and for 70% of spectively, but the Hypertension was tory of preeclamp- ported. The prevalence of diabetes and the controls, said Dr. Drost, a researcher in women with a his- seen in 44% of sia and 6% in the hypercholesterolemia was similar in the the cardiology department at the Isala tory of preeclamp- women with a controls, a signifi- two groups at follow-up. Clinics in Zwolle, the Netherlands. sia had a higher av- history of cant difference. However, the prevalence of metabol- At a screening examination performed erage waist preeclampsia and In a multivariate ic syndrome at follow-up reached 18% in a mean of 9-11 years following the index circumference, 87 17% of controls analysis that con- the women who had preeclampsia and pregnancy, the average blood pressure of cm, compared 9-11 years later. trolled for differ- 9% in the control women. After adjust- the women who had preeclampsia was with 83 cm in the ences in age, years ment, this represented a 60% increased 127/86 mm Hg, compared with an aver- controls; and hip DR. DROST following pregnan- risk for metabolic syndrome in the age of 119/79 in the controls. The preva- circumference, 104 cy, and waist cir- women with a history of preeclampsia lence of hypertension was 44% in the cm, compared with 100 cm in the con- cumference, the women with a history of that fell short of statistical significance. women with a history of preeclampsia trols. The prevalence of proteinuria, de- preeclampsia had a significant, 3.3-fold in- Dr. Drost had no disclosures. ■

Postmarketing cases of new onset and worsening heart failure have been reported during MULTAQ® treatment with MULTAQ. (dronedarone) Tablets Mom’s Smoking Hepatic: Serum hepatic enzymes and serum bilirubin increase: Hepatocellular liver injury, Dabigatran including acute liver failure requiring transplant, has been reported [see Warnings and Exposure to dabigatran is higher when it is administered with dronedarone than when it is Precautions (5.2)]. administered alone (1.7- to 2-fold). Ups Children’s 7 DRUG INTERACTIONS Other P-gP substrates are expected to have increased exposure when co-administered with Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and dronedarone. CYP 2D6 [see Clinical Pharmacology (12.3) in the full prescribing information]. Dronedarone’s Warfarin and losartan (CYP 2C9 substrates) blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and dronedarone Losartan CVD Risk can interact with drugs that are substrates of CYP 3A and CYP 2D6. No interaction was observed between dronedarone and losartan. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 Warfarin FROM THE EUROPEAN HEART JOURNAL and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport. When healthy subjects were administered dronedarone 600 mg twice daily, exposure to Pharmacodynamic interactions can be expected with beta-blockers; calcium antagonists and S-warfarin was higher than when warfarin was administered alone (1.2-fold). Exposure to R-warfarin was unchanged and there were no clinically significant increases in INR. digoxin [see Drug Interactions (7.1)]. More patients experienced clinically significant INR elevations (≥ 5) usually within 1 week after ealthy prepubescent children with In clinical trials, patients treated with dronedarone received concomitant medications including starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, Hmothers who smoked during preg- beta-blockers, digoxin, calcium antagonists (including those with heart rate-lowering effects), no excess risk of bleeding was observed in the dronedarone group. statins and oral anticoagulants. Postmarketing cases of increased INR with or without bleeding events have been reported in nancy have higher systolic blood pressures 7.1 Pharmacodynamic Interactions warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in and lower HDL cholesterol levels than do Drugs prolonging the QT interval (inducing Torsade de Pointes) patients taking warfarin. children born to women who do not Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic Theophylline (CYP 1A2 substrate) antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contrain- Dronedarone does not increase steady state theophylline exposure. smoke while pregnant, Dr. Julian G. Ayer dicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia [see Oral contraceptives of the University of Sydney, and his col- Contraindications (4)]. No decreases in ethinylestradiol and levonorgestrel concentrations were observed in healthy subjects receiving dronedarone concomitantly with oral contraceptives. leagues, reported in a longitudinal study. Digoxin 8 USE IN SPECIFIC POPULATIONS Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased 8.1 Pregnancy “Cholesterol levels tend to track from AV-node conduction). In clinical trials, increased levels of digoxin were observed when Pregnancy Category X [see Contraindications (4)] childhood to adulthood, and studies have dronedarone was co-administered with digoxin. Gastrointestinal disorders were also increased. MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, Because of the pharmacokinetic interaction [see Drug Interaction (7.3)] and possible pharma- dronedarone was teratogenic in rats at the maximum recommended human dose (MRHD), and shown that for every 0.025-mmol/L in- codynamic interaction, reconsider the need for digoxin therapy. If digoxin treatment is continued, in rabbits at half the MRHD. If this drug is used during pregnancy or if the patient becomes crease in HDL levels, there is an approx- halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. pregnant while taking this drug, the patient should be apprised of the potential hazard to the imately 2%-3% reduction in the risk of Calcium channel blockers fetus. When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on coronary heart disease,” Dr. David Cel- Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate 2 dronedarone’s effects on conduction. amg/m basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused ermajer, Scandrett Professor of Cardiol- Give low doses of calcium channel blockers initially and increase only after ECG verification of carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior ogy at the university, who led the study, good tolerability [see Drug Interactions (7.3)]. vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). said in a statement. “If we extrapolate Beta-blockers When2 pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on a In clinical trials, bradycardia was more frequently observed when dronedarone was given in mg/m basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and this, we can suggest that the difference of combination with beta-blockers. vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis). 0.15 mmol/L between children of smok- Give low dose of beta-blockers initially, and increase only after ECG verification of good ≥ ≥ tolerability [see Drug Interactions (7.3)]. Actual animal doses: rat ( 80 mg/kg/day); rabbit ( 20 mg/kg) ing mothers versus nonsmoking mothers 7.2 Effects of Other Drugs on Dronedarone 8.3 Nursing Mothers It is not known whether MULTAQ is excreted in human milk. Dronedarone and its metabolites might result in a 10%-15% higher risk for Ketoconazole and other potent CYP 3A inhibitors are excreted in rat milk. During a pre- and post-natal study in rats, maternal dronedarone coronary disease in the children of smok- Repeated doses of ketoconazole, a strong CYP 3A inhibitor, resulted in a 17-fold increase in administration was associated with minor reduced body-weight gain in the offspring. Because dronedarone exposure and a 9-fold increase in Cmax. Concomitant use of ketoconazole as well many drugs are excreted in human milk and because of the potential for serious adverse ing mothers.” as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, reactions in nursing infants from MULTAQ, a decision should be made whether to discontinue Results showed that children born to and nefazodone is contraindicated [see Contraindications (4)]. nursing or to discontinue the drug, taking into account the importance of the drug to the mother Grapefruit juice [see Contraindications (4)]. mothers who smoked during pregnancy Grapefruit juice, a moderate inhibitor of CYP 3A, resulted in a 3-fold increase in dronedarone 8.4 Pediatric Use had lower HDL cholesterol (1.32 vs. 1.50 Safety and efficacy in children below the age of 18 years have not been established. exposure and a 2.5-fold increase in Cmax. Therefore, patients should avoid grapefruit juice beverages while taking MULTAQ. 8.5 Geriatric Use mmol/L), higher triglycerides (1.36 Rifampin and other CYP 3A inducers More than 4500 patients with AF or AFL aged 65 years or above were included in the MULTAQ vs.1.20 mmol/L) and higher systolic Rifampin decreased dronedarone exposure by 80%. Avoid rifampin or other CYP 3A inducers clinical program (of whom more than 2000 patients were 75 years or older). Efficacy and safety blood pressure (102.1 vs. 99.9 mm Hg). such as phenobarbital, carbamazepine, phenytoin, and St John’s wort with dronedarone were similar in elderly and younger patients. because they decrease its exposure significantly. 8.6 Renal Impairment When postnatal ETS exposure and oth- Patients with renal impairment were included in clinical studies. Because renal excretion of Calcium channel blockers dronedarone is minimal [see Clinical Pharmacology (12.3) in the full prescribing information],no er confounders such as breastfeeding du- Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure dosing alteration is needed. ration, physical inactivity, and maternal by approximately 1.4-to 1.7-fold [see Drug Interactions (7.1, 7.3)]. 8.7 Hepatic Impairment Pantoprazole Dronedarone is extensively metabolized by the liver. There is little clinical experience with exposure to passive smoking during Pantoprazole, a drug that increases gastric pH, did not have a significant effect on dronedarone moderate hepatic impairment and none with severe impairment. No dosage adjustment is pregnancy were factored into the study, pharmacokinetics. recommended for moderate hepatic impairment [see Contraindications (4) and Clinical 7.3 Effects of Dronedarone on Other Drugs Pharmacology (12.3) in the full prescribing information]. the children still had lower HDL choles- Statins 10 OVERDOSAGE terol (a difference of –0.22 mmol/L) but Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively. In the event of overdosage, monitor the patient’s cardiac rhythm and blood pressure. Treatment Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin should be supportive and based on symptoms. had no significant difference in systolic label recommendations for use with CYP 3A and P-gP inhibitors such as dronedarone. It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodi- blood pressure. When excluding post- Calcium channel blockers alysis, peritoneal dialysis or hemofiltration). natal ETS exposure and including all Dronedarone increases calcium channel blocker (verapamil, diltiazem or nifedipine) exposure There is no specific antidote available. by 1.4- to 1.5-fold [see Drug Interactions (7.1)]. Issued March 2011 other confounders, the difference was Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range Manufactured by Sanofi Winthrop Industrie about –0.14 mmol/L (Eur. Heart J. 2011 Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A 1,ruedelaVierge substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations 33440 Ambares, France June 21 [doi:10.1093/eurheartj/ehr174]). and adjust dosage appropriately. Included in the study were 328 chil- ©sanofi-aventis, 2011 Beta-blockers and other CYP 2D6 substrates dren from Sydney who were enrolled Dronedarone increased propranolol exposure by approximately 1.3-fold following single dose All rights reserved. administration. Dronedarone increased metoprolol exposure by 1.6-fold following multiple dose MULTAQ is a trademark of sanofi-aventis. into the Childhood Asthma Prevention administration [see Drug Interaction (7.1)]. Other CYP 2D6 substrates, including other beta- blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have The brands listed are the registered trademarks of their respective owners and are not Study (CAPS) at birth and who under- increased exposure upon co-administration with dronedarone. trademarks of sanofi-aventis U.S. LLC. went a lipoprotein study at age 8 years. P-glycoprotein substrates Researchers received funding from an Digoxin sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Dronedarone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter [see Drug Australian Government National Health Interactions (7.1)]. DRO-BPLR-SA-MAR11 and Medical Research Council Project Grant and a Pfizer CVL Grant. The re- searchers reported no relevant financial disclosures. –Nancy Pham